Tetrahydrooxazine derivatives

ABSTRACT

Tetrahydrooxazine derivatives and processes for the preparation thereof are disclosed. These tetrahydrooxazine compounds are useful as intermediates in the preparation of psychosedative agents.

United States Patent Edenhofer Dec. 16, 1975 TETRAHYDROOXAZINEDERIVATIVES 75 Inventor: Albrecht Edenhofer, Riehen, [561 ReferencesCited Switzerland UNITED STATES PATENTS [73] Assignee; H ff L Roche IncN fl y 2,537,854 1/1951 Plati et a1 260/297 NJ 3,337,546 8/1967Malatestmic et a]. 260/244 3,723,445 3/1973 Edenhofer et a]. 260/244[22] Filed: Jan. 13, 1975 3,833,576 9/1974 Edenhofer et al. 260/244 [21]Appl' 540622 Primary ExaminerAlbert T. Meyers Related US. ApplicationData Assistant ExaminerD. W. Robinson [62] Division of Ser. N0. 362,636,May 21, 1973, Pat. NO. Alwmey, Agent, or Firmsamuel Welt; Bernard3,879,405, which is a division of Ser. No. 148,119, Leon; Frank P. m nMay 28, 1971, Pat. No. 3,758,483.

[57] ABSTRACT [30] Foreign Appmfanon Pnonty Data Tetrahydrooxazinederivatives and processes for the June 19, Switzerland preparationthereof are These tetrahydroox azine compounds are useful asintermediates in the [52] US. Cl. 260/244 preparation f psychosedativeagents [51] Int. Cl. C07D 87/00 58 Field of Search 260/244 R 1 Clam, N0Drawmgs TETRAHYDROOXAZINE DERIVATIVES This is a division of applicationSer. No. 362,636 filed /21/73, now US. Pat. No. 3,879,405, which is adivision of Ser. No. 148,119 filed 5/28/71 now US Pat. No. 3,758,483.

DESCRIPTION OF THE INVENTION The present invention relates to novelchemical compounds and to processes for the preparation thereof, saidcompounds having valuable therapeutic properties. More particularly, thepresent invention is concerned with new tetrahydropyridine derivativesof the general formula wherein R signifies hydrogen, lower alkyl, loweralkanoyl, lower alkylsulfonyl, cycloalkyl or cycloalkyllower alkyl; Rsignifies hydrogen, lower alkyl, cycloalkyl or cycloalkyllower alkyl; Rsignifies fluorine, chlorine or lower alkoxy; X signifies an oxygen atomor a sulfur atom and the pharmaceutically acceptable acid addition saltsthereof.

As used herein, either alone or in combination such as in loweralkyl-sulfonyl, the term lower alkyl comprehends straight or branchedchain hydrocarbon groups having from 1 to 7 carbon atoms, preferablyfrom 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,n-hexyl and the like. The term lower alkoxy designates straight orbranched chain saturated hydrocarbonoxy groups containing from 1 to 7carbon atoms, preferably from 1 to 4 carbon atoms, such as methoxy,ethoxy, propoxy and the like. The term lower alkanoyl denotes theresidue of a straight or branched chain aliphatic carboxylic acid,containing from 1 to 7 carbon atoms, for example formyl, acetyl,propionyl, isobutyryl and n-valeryl. The term cycloalkyl encompassescyclic hydrocarbon groups having from 3 to 6 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of thecycloalkyl-lower alkyl groups include cyclopropyl-methyl,cyclopropyl-ethyl and the like.

A preferred class of compounds falling within the scope of formula I arethose wherein X represents an oxygen atom, i.e., compounds of theformula wherein R,R are as described above.

Another preferred class of compounds falling within the scope of formulaI are those wherein R signifies fluorine, i.e., compounds of the formulawherein R R and X are as described above.

Particularly preferred of the compounds of formula 1 above are thosewherein R represents a lower alkanoyl group, preferably the acetylgroup, R represents hydrogen, R represents fluorine and X representsoxygen. Most preferred of the compounds of formula I is: 42-[4-(p-fluorophenyl)-3,6-dihydro-l(2l-I)-pyridyl]- ethoxy acetanilide.

The novel compounds of formula 1 can be prepared following a variety ofsynthetic routes.

A. In one such process aspect, the compounds of formula I above can beprepared by condensing a compound of the general formula wherein R R andX are as described above and Z represents a suitable leaving group witha compound of the general formula wherein R is as described above.

Suitable leaving groups in the starting materials of formula II aboveinclude a halogen atom, preferably chlorine or bromine, a loweralkylsulfonyloxy group, preferably mesyloxy, an arylsulfonyloxy group,preferably tosyloxy or benzene-sulfonyloxy, or the group N(R A in whichR signifies lower alkyl and A signifies the anion of an acid.

The condensation of a compound of formula II with a compound of formulaIII is expediently effected in the presence of a polar organic solvent.Suitable for this purpose are lower alkanols such as methanol, ethanol,isopropanol and the like; cyclic ethers such as tetrahydrofuran anddioxane; and dimethylformamide or di-' methyl sulfoxide. Thecondensation is advantageously effected at a temperature between roomtemperature and the reflux temperature of the reaction mixture. Where,in the starting material of formula II the leaving group designated as Zrepresents a halogen atom or a lower alkyl or aryl-sulfonyloxy group,the condensation reaction is preferably carried out in the presence ofan acid binding agent, for example in the presence of an alkalicarbonate such as potassium carbonate.

III

The starting materials of formula II above may be prepared by reacting acompound of the formula XII wherein R R and X are as described abovewith a 2-halo-ethanol of the formula haloCI-I CI-I OH to yield acompound of the formula X-CH CH H Il -Iii VI I wherein R R and X are asdescribed above.

The compound of formula VI so obtained can then be reacted with ahalogenating agent, such as thionyl chloride to obtain the compound offormula II wherein Z signifies halogen. This halogenation reaction ispreferably effected in the presence of an inert organic solvent such aschloroform or benzene at a temperature between about room temperatureand the reflux temperature of the reaction mixture.

Alternately, the compound of formula VI above can be reacted with analkylor arylsubstituted sulfonic acid halide, preferably the chloride,to yield the desired compound of formula II wherein Z signifies analkylor aryl-sulfonyloxy group. This reaction is expediently effected inthe presence of an acid binding agent at a temperature between about 0Cand room temperature.

The compounds of formula II above wherein Z represents the group N(R A Rand A being as defined above, can be prepared by amination of thecorresponding compounds of formula II wherein Z signifies halogen. Thisamination can be effected by reacting the halo-substituted compound offormula II with a dialkylamine, preferably dimethylamine; this reactionis expediently effected in a closed vessel at an elevated temperature,for example between about 50 and l50C. The product obtained as a resultof this amination is subsequently quaternized by reaction with analkylating agent such as an alkyl chloride, alkyl bromide or dialkylsulfate, preferably methyl chloride, methyl bromide or dimethyl sulfate.The quaternization is preferably carried out at a temperature of fromabout room temperature to about 75C. Both the amination andquaternization are expediently carried out in the presence of an inertsolvent such as an alkanol, i.e., methanol, or in dioxane or benzene.

The starting materials of formula II wherein X signifies oxygen and theleaving group Z is a halogen atom may also be prepared by reacting acompound of formula IV wherein X is oxygen with an excess of a 1,2-dihaloethane, preferably l,2-dibromoethane in the presence of an excessof aqueous alkali, preferably caustic soda. This reaction is preferablycarried out at a temperature between room temperature and the boilingpoint of the reaction mixture. 5 The starting materials of formula IIIwherein R signifies lower alkoxy can be prepared, for example, byemploying a Grignard reaction. Thus, for instance, the reaction betweenN-benzyl-4-piperidone and p-methoxyphenyl magnesium bromide, followed byhydrogenolytic cleavage of the benzylgroup and treatment with adehydrating agent such as, for example, thionyl chloride or alcoholichydrochloric acid, yields the desired compound of formula III wherein Ris methoxy.

B. In another process aspect of the present invention, the compounds offormula I above can be prepared by reacting a compound of the Formulawherein R R and X are as described above and M signifies an alkali metalor a halomagnesium radical with a compound of the formula wherein R isas described above and L is a suitable leaving group.

The substituent M in the starting materials of formula VII preferablyrepresents an alkali metal, especially sodium or potassium. In addition,M can also represent a halo-magnesium radical such as thebromo-magnesium or chloro-magnesium radical.

The leaving group in the compounds of formula VIII designated by thesymbol L is preferably a halogen atom, especially chlorine or bromine,or an alkylor aryl-sulfonyloxy group, especially mesyloxy or tosyloxy.

The reaction between a compound of formula VII wherein M represents analkali metal and a compound of formula VIII effected in the presence ofan alkali alkanolate, for example sodium ethanolate, in thecorresponding alkanol, for example, ethanol. When the M substituent inthe compounds of formula VII represents a halo-magnesium radical, thereaction of this formula VII compound with a compound of formula VIII ispreferably carried out in a polar organic solvent such as in an ether,i.e. dimethyl ether, tetrahydrofuran or dioxane. This reaction ispreferably carried out at a temperature between room temperature and thereflux temperature of the reaction mixture.

The starting materials of formula VIII are expediently prepared byreacting a compound of formula III above with a 2-halo-ethanol,preferably 2-chloro-ethanol, to yield a compound of the formula whereinR is as described above. This reaction is preferably effected in polarsolvent such as, for example, an alkanol, i.e., methanol, ethanol andthe like, dimethylformamide or dimethyl sulfoxide. It is preferable tocarry out this reaction in the presence of an acid binding agent, forexample, in the presence of an alkali carbonate such as potassiumcarbonate and at a temperature between room temperature and the refluxtemperature of the reaction medium. The compound of formula IX thusobtained can subsequently be reacted with a halogenating agent such asthienyl chloride to yield the desired starting material of formula VIIIin which L represents a halogen atom.

This halogenation is preferably effected in the presence of an inertsolvent, for example benzene or chloroform, at a temperature betweenroom temperature and the reflux temperature of the reaction mixture.

The compound of formula IX above can alternatively be reacted with analkylor arylsubstituted sulfonic acid halide, preferably the chloride,to give the desired starting material of formula VIII in which Lrepresents an alkylor arylsubstituted sulfonyloxy group. This reactionis expediently effected in the presence of an acid binding agent, forexample, pyridine or triethylamine, at a temperature between about C androom temperature.

C. In a further process aspect of the present invention, the desiredcompounds of formula I above can be prepared by dehydrating a compoundof the formula wherein R R R and X are as described above.

The dehydration of the compounds of formula X above is effectedemploying conventional techniques, as for example by treating saidcompound with a standard dehydrating agent. Suitable dehydrating agentsfor this purpose include acetic acid anhydride, acetyl chloride, thionylchloride, p-toluenesulfonic acid, sulfuric acid, aluminum oxide, calciumchloride and the like. This dehydration reaction is expediently effectedin an inert organic solvent such as chloroform, toluene, or glacialacetic acid and a temperature between room temperature and the refluxtemperature of the reaction mixture.

The starting materials of formula X can, for example, be prepared byreacting a compound of formula II above with an appropriatelysubstituted 4-hydroxy-4- phenyl-piperidine. This reaction is preferablyeffected in a polar solvent such as an alkanol, i.e., methanol, ethanoland the like, dimethylforrnamide, dimethyl sulfoxide or tetrahydrofuranand in the presence of an acid binding agent such as an alkalicarbonate, preferably potassium carbonate. The temperature range forthis reaction is preferably between room temperature and the refluxtemperature of the reaction medium.

LII

D. In another process aspect of this invention, the desired compounds offormula I above can be prepared by treating a compound of the generalformula o on pow ow-raj R3 wherein R R R and X are as described abovewith a mineralacid.

The treatment of the starting material of formula XI with a mineral acidis preferably carried out using concentrated hydrochloric acid. In sodoing, the acid treatment of the formula XI compound is effected at atemperature between about 0C and the reflux temperature of the reactionmixture, preferably at an elevated temperature, for a prolonged period,for example between three to six hours. It should be noted that anylower alkanoyl group present in the starting material of formula XI asthe R substituent will be saponified under these reaction conditions.

E. In a further process aspect of this invention, the compounds offormula I above wherein R and R each signify hydrogen can be prepared byreducing a compound of the general formula 0 XII wherein R and X are asdescribed above.

The reduction of the starting material of formula XII is preferablycarried out by treatment of said compound with hydrazine in the presenceof a noble metal catalyst such as palladium on charcoal or platinumoxide. Alternatively, the reduction can also be carried out by treatmentof the formula XII compound with sodium dithionite or with nascenthydrogen which can be provided, for example, by using a mineral acidsuch as hydrochloric acid and a metal which is capable of liberatinghydrogen such as zinc or irom. This reduction is expediently effected inthe presence of a lower alkanol preferably ethanol, or in a cyclicether, preferably tetrahydrofuran. The reduction is preferably carriedout 7 at a temperature between room temperature and the refluxtemperature of the reaction mixture.

The starting materials of formula XII can be prepared, for example, bycondensing a 4-nitro-l-( Z-haloethoxy or Z-halo-ethylthio)-benzene witha compound of formula III above. The conditions employed for thecondensation of the appropriately substituted benzene compound with theformula III compound are essentially the same as those described inprocess aspect A above for the condensation of compounds of formulae IIand III.

F. In another process aspect of the instant invention, a compound of thegeneral formula RIO-N l xIII wherein R and X are as described above; Rsignifies hydrogen, lower alkyl, lower alkanoyl, cycloalkyl orcycloalkyl-lower alkyl; R signifies hydrogen, lower alkyl, cycloalkyl orcycloalkyl-lower alkyl; or R and R together each represent an oxygenatom is reduced to yield a compound of the formula wherein R R and X areas described above and R signifies hydrogen, lower alkyl, loweralkanoyl, cycloalkyl or cycloalkyl-lower alkyl.

The starting material of formula XIII is reduced by treatment of saidcompound with a complex metal hydride, preferably lithium aluminumhydride. This reduction is preferably effected in an organic solventsuch as ether, tetrahydrofuran, dioxane or diglyme, and at a temperaturebetween about C and the reflux temperature of the reaction mixture. If,in the starting materials of formula XIII, R and R each signify anoxygen atom, the nitro group present in the starting material is firstreduced following the procedures set forth in process aspect E above,and then the acid amide function is reduced as described above.

The starting materials of formula XIII can, for example, be prepared byreacting a compound of the general formula X-CH; CO-halo XIV RIO-

G. The compounds of formula I above wherein R signifies lower alkyl,lower alkanoyl, lower alkylsulfonyl cycloalkyl or cycloalkyl-lower alkylcan be prepared following conventional techniques by introducing thedesired R, substituent into the corresponding compound of the formula Iwherein R signifies hydrogen, i.e., into a compound of the formulawherein R R and X are as described above.

The introduction of the desired R substituent into the compound offormula Id above can be affected following conventional alkylating,alkanoylating or alkylsulfonylating techniques. Thus, for example, alower alkyl, cycloalkyl or cycloalkyl-lower alkyl group can beintroduced using standard alkylating procedures as by reacting theformula Id compound with an appropriate alkylating agent such as methyliodide, cyclopropylbromide, dimethyl sulfate and the like. In a furtherexample, the compound of formula Id can be treated with an appropriateacid halide or acid anhydride such as acetyl chloride, acetic anhydride,cyclopropane carboxylic acid chloride or methane sulfonic acid chlorideto yield the correspondingly substituted compound of formula I. Thetreatment with an acid chloride is preferably effected in the presenceof an acid-binding agent, for example, a tertiary organic base such astriethylamine or pyridine, and an inert organic solvent such as benzene,chloroform, tetrahydrofuran or dimethyl sulfoxide and at a temperaturebetween room temperature and the reflux temperature of the reactionmedium. The treatment with an acid anhydride is preferably effected in apolar protonic solvent such as an alkanol, for example methanol, or inthe presence of a dilute alkanecarboxylic acid, for example, diluteacetic acid. This reaction is expediently carried out at a temperaturebetween about 0C. and about 50C., preferably at room temperature.

This process aspect represents a preferred procedure for the preparationof the compounds of formula 1 above wherein R signifies a loweralkyl-sulfonyl group. It is also the preferred procedure for introducinga lower alkylsulfonyl group, when desired, into the starting materialsof formulae II, VII, X and XI above wherein R signifies hydrogen.

The compounds of formula I above wherein R signifies a lower alkanoylgroup can be saponified following conventional techniques, as forexample, by treating said compound with dilute aqueous caustic alkali orwith aqueous acid. It is advantageous to use about 20 percenthydrochloric acid at an elevated temperature, especially at the refluxtemperature of the reaction mixture.

The compounds of formula I above are basic and thus form acid additionsalts with both pharmaceutically acceptable organic or inorganic acids,for example, with hydrohalic acids such as hydrochloric acid,hydrobromic acid and hydroiodic acid, with other mineral acids such assulfuric acid, phosphoric acid and nitric acid, as well as with organicacids such as tartaric acid, citric acid, oxalic acid, camphorsulfonicacid, ethanesulfonic acid, toluenesulfonic acid, salicyclic acid,ascorbic acid, maleic acid, mandelic acid and the like. Preferred saltsare the hydrohalides, especially the hydrochlorides. The acid additionsalts are preferably manufactured in a suitable solvent such as ethanolor acetonitrile by treatment of the free base with the correspondingnon-aqueous acid.

The compounds of formula I above are, in part, crystalline substanceswhich are relatively readily soluble in dimethyl sulphoxide,dimethylformamide, in chlorinated hydrocarbons such as, for example,chloroform or methylene chloride and in alkanols such as methanol orethanol, but which are relatively insoluble in water.

The acid addition salts of the compounds of formula I are crystallinesubstances. They are readily soluble in dimethyl sulphoxide,dimethylformamide, in alkanols such as methanol or ethanol and, usually,also in water. They are relatively insoluble in benzene, petroleum etherand in chlorinated hydrocarbons such as, for example, chloroform ormethylene chloride.

As indicated above, the compounds of formula I above exhibitpsychosedative activity. The p sychosedative activity of thetetrahydroxyridine derivatives of formula I is demonstrated in warmblooded animals using the standard open field test with rats[Psychopharmacologia I, 389-392 (1960)]. The dosage which caused a 50percent decrease (in comparison to the untreated controls) in the numberof diameter crossings is expressed as the ED The results of the test forrepresentative compounds of formula I are shown in the following Table:

The tetrahydropyridine derivatives provided by this invention can beused as medicaments; for example, in the form of pharmaceuticalpreparations which contain them in association with a compatiblepharmaceutical carrier. This carrier can be an organic or inorganicinert carrier material which is suitable for enteral or parenteralapplication such as, for example, gelatin,

10 gum arabic, lactose, starches, magnesium stearate, talc, vegetableoils, polyalkylene glycols etc. The pharmaceutical preparations arepreferably made up in solid form (e.g., as tablets, dragees,suppositories or capsules). They can also contain yet othertherapeutically valuable substances.

Expedient pharmaceutical dosage forms contain about 5-100 mg. of acompound of formula I. Expedient oral dosage ranges lie at about 0.1mg/kg/day to about 10 mg/kg/day. However, the stated ranges can beextended upwards or downwards depending on the individual requirement ofthe patient or the directions given by the specialist.

The starting materials of formulae X, XI, XII, and XIII are novel and assuch form apart of the present invention. The following examples furtherillustrate the scope of the noted invention. Unless otherwise indicated,the temperature stated are in degrees centigrade.

EXAMPLE 1 I 21.4 g. of 4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridinehydrochloride, 25.8 g. of 4'-(2-bromoethoxy)acetanilide, 30 g. ofpotassium carbonate and a few crystals of potassium iodide are heatedunder reflux conditions in 200 ml. of ethanol and 20 ml. of water for 24hours. While still hot, the mixture is decanted from the aqueous phase,ml. of water are added and the mixture is allowed to cool, with crude4'-{2-[4-(pfluorophe nyl )-3 ,6-dihydro- 1 (2H )-pyridyl ]ethoxy}acetanilide crystallizing out of solution. This is dissolved in amixture of ml. of methanol and 50 ml. of acetic acid ethyl ester andconverted by addition of alcoholic hydrochloric acid, until the mixturebecomes acidic, into the hydrochloride, which crystallizes after theaddition of 100 ml. of acetic acid ethyl ester. The hydrochloride meltsat 2l42l6C. (dec.).

Following similar procedures to those set forth above, the followingcompounds may also be prepared:

a. 4'-{ 2-[4-(p-fluorophenyl)-3,6-dihydrol (2I-I)pyridyl]ethoxy}propionanilide hydrochloride, m.p. 244-246C. (frommethanol-acetic acid ethyl ester) from 4'-(2-bromoethoxy)-propionanilideand 4-(pfluorophe nyl 1 ,2,3 ,6-tetrahydropyridine;

b. 4'-{ 2-[4 -(p-chlorophenyl)-3,6-dihydro- 1(2I-I)pyridyl]ethoxy}isobutyranilide hydrochloride, m.p. 239-246C. (frommethanol-acetic acid ethyl ester) from4'-(2-bromoethoxy)-isobutyranilide and 4- (p-chlorophenyl)- l ,2,3,6-tetrahydro pyridine;

c. 4- 2-[4-(p-fluorophenyl)-3 ,6-dihydro- 1(2H)pyridyl]ethoxy}-isobutyranilide hydrochloride, m.p. 239241C. (frommethanol-acetic acid ethyl ester) from 4-(2-bromoethoxy)-isobutyranilideand 4- (p-fluorophenyl )-1 ,2,3 ,6-tetrahydropyridine;

d. 4'-{2-[4-(p-chlorophenyl)-3,6-dihydro- 1(2H)pyridyl] ethoxy}acetanilide hydrochloride, m.p. 228229C. (from methanol-acetic acidethyl ester) from 4-(2-bromoethoxy)-acetani1ide and 4-(p-chlorophenyl)-l,2,3,6-tetrahydropyridine;

e.4- {2-[4-(p-methoxyphenyl)-3 ,6-dihydro- 1 (2H)- pyridyl]ethoxy}acetanilide, m.p. l63-164C. (from methanol) from4'-(2-bromoethoxy)acetanilide and 4-( p-methoxyphenyl l ,2,3,6-tetrahydropyridine.

The 4-(2-bromoethoxy)propionanilide employed as a starting material canbe manufactured as follows:

82.5 g. of p-propionamidophenol are introduced into a solution of 20 g.of sodium hydroxide in 20 ml. of water and 400 ml. of ethanol and, withstrong stirring,

treated with 470 g. of 1,2-dibromoethane. The mixture is heated underreflux conditions for 3 hours and the dibromoethane is driven off withthe aid to steam. The crude 4'-(2-bromoethoxy)propionanilide whichprecipitates is washed with water and recrystallized from ethanol withthe addition of water. The compound melts at 151C.

The 4-( 2-bromoethoxy)isobutyranilide employed as starting material canbe manufactured in a manner analogous to that described above, mp. 143C.(from ethanol).

EXAMPLE 2 1.8 G. of 4'-[(2-chloroethyl)thio]acetanilide, 2.7 g. of4-(p-fluorophenyl)-1,2,3 ,6-tetrahydropyridine, 4.5 g. of potassiumcarbonate and a few crystals of potassium iodide are heated under refluxconditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. Thesolvent is evaporated under reduced pressure, the residue is taken up inchloroform and washed with water. From the organic phase there isobtained crude 4- {[2-[4-(pfluorophenyl )-3 ,6-dihydro- 1 21-1 )-pyridyl-ethyl ]thio}acetanilide which melts at l50152C. after recrystallizationfrom acetic acid ethyl ester.

The 4'-[(2-chloroethyl)thio]-acetanilide employed as starting materialcan be manufactured as follows:

A solution of 17.5 g. of 4-[(2-hydroxyethyl)thio]- acetanilide in 500ml. of absolute benzene is treated dropwise with stirring with 17.5 g.of thionyl chloride and heated under reflux conditions for 1 hour. Thecrude 4'-[(2-chloroethyl)-thio]-acetanilide remaining behind afterevaporation of the solvent under reduced presssure melts at 153l55C.after repeated crystallization from acetic acid ethyl ester. A furthercrystallization can be obtained from the mother liquor by adsorption onsilica gel and elution with methylene chloride.

EXAMPLE 3 7.8 G. of 4'-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2l-1)-pyridyl]-ethoxy}acetanilide and 40 ml. of about 20% hydrochloricacid are heated under reflux conditions for 1 hour. The crudep-{2-[4-(p-fluorophenyl)- 3,6-dihydro-l(2H)-pyridyl]ethoxy} anilinedihydrochloride hydrate which precipitates on cooling melts at 180183C.After recrystallization from ethanolacetic acid ethyl ester-diethylether.

EXAMPLE 4 0.8 G. of p-{2-[4-(p-fluorophenyl)-3,6-dihydrol(2H)-pyridyl]ethoxy}aniline aredissolved in ml. of 3-N acetic acid and treated with 0.5 g. of aceticacid anhydride. The solution is stored at room temperature for 12 hoursand subsequently evaporated under re! duced pressure. The residue istaken up in chloroform, this extract with l-N caustic soda andevaporated. The residual crude 4'- 2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]ethoxy acetanilide melts at 139C. after recrystallizationfrom acetic acid ethyl ester.

EXAMPLE 5 A solution of 4.5 g. of p-{2-[4-(p-fluorophenyl)-3,6-dihydro-l(2l-l)-pyridyl]ethoxy}aniline in 15 ml. of chloroform istreated with 2 g. of triethylamine. A solution of 1.7 g. ofmethanesulfonic acid chloride in 10 ml. of chloroform is added theretowith stirring and cooling at a temperature range of O10C. The reactionmixture is allowed to stand at room temperature for 12 hours. It iswashed with water and the solvent is evaporated. The residual crude4-{2-[4-(p-fluorophenyl)- 3,6-dihydro-1(2l-1)-pyridyl]ethoxy}-methanesulfonanilide melts at137l39C. after recrystallization from methanol.

EXAMPLE 6 0.1 G. of 4'-{2-[4-(p-fluorophenyl)-4-hydroxypiperidino]ethoxy}acetani1ide are dissolved in 30 ml. of chloroform with slightheating and 0.2 g. of thionyl chloride are added. The mixture is heatedunder reflux conditions for 4 hours. The crude 4'-{2-[4-(p-fluorophenyl)-3 ,6-dihydro- 1 (21-1 )-pyridyl -ethoxy acetan ilide hydrochlorideremaining after evaporation of the solvent melts at 2132l5C. (dec.)after recrystallization from methanol-diethyl ether.

The 4 {2-[ 4-( p-fluorophenyl )-4-hydroxypiperidino]ethoxy}-acetanilideemployed as starting material can be manufactured as follows:

1.3 G. of 4-(p-fluorophenyl)-4-hydroxypiperidine, 1.85 g. of4'-(2-bromoethoxy)-acetanilide, 1 g. of potassium carbonate and a fewcrystals of potassium iodide are heated under reflux conditions in 20ml. of isopropanol for 24 hours. The residue remaining after evaporationof the solvent is taken up in chloroform and washed with water. Thecrude 4'-{2-[4-(p-fluorophenyl)-4-hydroxypiperidino]-ethoxy}acetanilideobtainable from the organic phase melts at 174-175C. afterrecrystallization twice from isoproponol EXAMPLE 7 0.2 G. of4'-{2-[6-(p-fluorophenyl)-dihydro-6-methyl-2H-1,3 -oxazin-3 4H )-y1]ethoxy ac etanilide hydrochloride and 2 ml. of conc. hydrochloric acidare heated on the steam bath for 4 hours. The excess hydrochloric acidis evaporated under reduced pressure and the residue brought tocrystallization with ethanolacetic acid ethyl ester. The p-{2-[4-(p-fluorophenyl)- 3,6dihydrol(2H)-pyridyl]ethoxyl} anilinedihydrochloride hydrate obtained melts at 180l83C. afterrecrystallization from ethanol-acetic acid ethyl ester.

The 4'- {2-[6-(p-fluorophenyl)-dihydro-6-methyl-21-1-1,3-oxazin-3(4I-l)-y1]ethoxy} -acetanilide employed as startingmaterial can be manufactured as follows:

5.2 G. of 4'-(2-bromoethoxy)acetanilide, 4 g. of 6-methyl-6-(p-fluorophenyl)-tetrahydro-1,3-oxazine, 5 g. of potassiumcarbonate and a few crystals of potassium iodide are heated under refluxconditions in 50 m1. of ethanol for 16 hours. After evaporation of thesolvent under reduced pressure, the residue is dissolved in chloroformand washed with water. The crude product obtained from the organic phaseis adsorbed on silica gel and purified by elution with methylenechlorideether (1:1 There is obtained an oil which is converted into thehydrochloride as previously described. The pure 4 2-[ 6-(p-fluorophenyl)-dihydro-6-methyl-2 l-l- 1,3-oxazin-3(4ll)-yl]ethoxy} acetanilide meltsat 180C. (dec.) after recrystallization from acetic acid ethyl ester.

EXAMPLE 8 A solution of 0.3 g. of l-[(p-aminophenoxy)acetyl]-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine in 5 ml. of absolutetetrahydrofuran is added dropwise at room temperature with stirring andnitrogen gassing to a suspension of 0.3 g. of lithium aluminum hydridein 10 ml. of absolute tetrahydrofuran. The stirring is continued at roomtemperature for 16 hours and water is cau- 13 tiously added, initially,dropwise. After filtration, the mixture is extracted with chloroform.The oily residue is purified by column chromatography on silica gel withdiethyl ether-acetic acid ethyl ester (1:1) as eluting agent andconverted into the hydrochloride as previously described. Thep-{2-[4-(p-fluorophenyl)-3,6-

dihydro-l(2H)-pridylethoxy} aniline dihydrochloride hydrate meltsat(H)-pyridyl]-l83C. after crystallization with ethanol-acetic acidethyl ester-ether.

The l-[ (p-aminophenoxy)-acetyl-4-(p-fluorophenyl)-l,2,3,-tetrahydropyridine employed as startingmaterial can be manufactured as follows:

A solution of 4.3 g. of p-nitrophenoxyacetic acid chloride in 10 ml. ofabsolute benzene is added dropwise with stirring and cooling to'asolution of 3.6 g. of p-fluorophenyl-l,2,3,6-tetrahydropyridine and 5 g.of triethylamine in 20 ml. of absolute benzene and the reaction mixtureis heated under reflux conditions for 1 hour. After cooling, thetriethylamine hydrochloride thereby precipitated is extracted with waterand the organic phase is washed with 1N hydrochloric acid and water. Thecrude 4-(p fluorophenyl)-l,2,3,6-tetrahydro-l-[(p-nitrophenoxy)acetyl]pyridine obtained after evaporation of the solvent melts atl34136C. after recrystallization from isopropanol.

2.3 g. of this compound and 2.5 g. of hydrazine hydrate are dissolved in50 ml. of absolute tetrahydrofuran. 0.2 g. of platinum dioxide are addedportionwise commencing the strong evolution of nitrogen. After cessationof the evolution of gas, the mixture is heated under reflux conditionsfor 15 hours and subsequently filtered. After evaporation of thesolvent, the residue is purified by column chromatography on silica gelwith methylene chloride as eluting agent. The 1-[(p-aminophenoxy)acetyl]-4-(p-fluorophenyl)- l ,2,3,6-tetrahydropyridine obtained from theeluate melts at l20l22C. after recrystallization from benzene.

EXAMPLE 9 0.3 g. of p-acetamidophenol are dissolved in a solution of0.12 g. of sodium in 10 ml. of absolute ethanol and 0.55 g. of 1-(2-chloroethyl)-4(p-fluorophenyl)- l,2,3,6-tetrahydropyridinehydrochloride are added thereto all at once. The reaction mixture isheated under reflux conditions for 24 hours, filtered from theprecipitated sodium chloride and the filtrate evaporated to dryness. Theresidue is adsorbed on silica gel and eluted with methylenechloride-ether (1:1). The 4'- {2-[4-(p-fluorophenyl)-3,6-dihydro-1 (2H)-pyridyl]-ethoxy}-acetanilide obtained from the eluate melts at 139C.after recrystallization from acetic acid ethyl ester.

The l-( 2-chloroethyl )-4-(p-fluorophenyl 1 ,2,3,6- tetrahydropyridineemployed as starting material can be manufactured as follows:

1 .77 g. of 4-(p-fluorophenyl)- l ,2,3,6-tetrahydropyridine, 0.8 g. ofethylene chlorohydrin, 1.2 g. of sodium carbonate and a few crystals ofsodium iodide are heated under reflux conditions in 10 ml. of ethanolfor 24 hours and filtered hot and the filtrate is evaporated to dryness.The residual oil is purified by column chromatography on silica gel withacetic acid ethyl esterethanol (1:1) as eluting agent. Thel-(2-hydroxyethyl)- 4-(p-fluorophenyl)- 1 ,2,3,6-tetrahydropyridineobtained from the eluate melts at 9698C. after recrystallization fromcyclohexane.

0.5 g. of l-(2-hydroxyethyl)-4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine are dissolved in 10 ml. of

' fluorophenyl l ,2,3 ,6-tetrahydropyridine EXAMPLE 10 0.2 g. ofpowdered iron is added to a solution of 0.34 g. of '4-(p-fluorophenyl)-l ,2,3,6-tetrahydro-1-[2-(pnitrophenoxy) ethyl]pyridine in a mixture of2 ml. of 1N hydrochloride acid, 10 ml. of ethanol and 10 ml. of water.The mixture is refluxed for 4 hrs., cooled and made alkalaine byadditionof 1N sodium hydroxide. After addition of 20 ml. of chloroform andcelite, the mixture is filtered. The organic phase is separated, driedand evaporated. The oily residue obtained is dissolved in ethyl acetateand converted to the hydrochloride by addition of ethanolic hydrogenchloride. The l-[2-(p-aminophenoxy)ethyl]-4-(p-fluorophenyl)-l,2,3,6-tetrahydropyridine dihydrochloride obtained in this way has m.p.180-l81 after recrystallization from ethanol/ethylacetate/ether.

The starting material may be prepared as follows:

A mixture of 2.15 g. of 4-(p-fluorophenyl)-l,2,3,6- tetrahydropyridinehydrochloride, 2.5 g. of p-(2- bromoethoxy)-nitrobenzene, 2.8 g. ofpotassium carbonate, 20 ml. of ethanol and 2 ml. of water is refluxedfor 3 days. After filtration the crude product crystallizes from the hotreaction mixture. It is purified by chromatography on silica gel usingmethylene chloride for elution. The4-(p-fluorophenyl)-1,2,3,6-tetrahydro-1-[2-(p-nitrophenoxy)ethyl]pyridine obtained melts at 104107 afterrecrystallization from ethanol.

EXAMPLE 11 Manufacture of capsules of the following composition:

hydrochloride 10 mg. Mannitol l 10 mg. Talcum 5 mg.

The active substance is homogeneously mixed with the talcum andmannitol, passed through a No. 5 sieve (mesh width about 0.23 mm) andagain thoroughly mixed. The mixture obtained is filled into No. 4gelatin capsules.

EXAMPLE 12 Manufacture of dragees of the following compositions:

hydrochloride 25 mg. Mannitol mg. Corn starch 20 mg. Talcum 5 mg.

The active substance is mixed with the mannitol and passed through a No.5 sieve (mesh width about 0.23 mm). A 10% aqueous paste is prepared fromthe corn starch and libifibgeneously mixed with the mannitolactivesubstance mixture. The slightly moist mash is passed through a No. 2sieve (mesh width about 1.0 mm). The granulate obtained is dried and,after the addition of the talcum, pressed to biconvex cores with aweight of 150 mg. The cores are coated with a sugar layer in the usualmanner by dredging.

I claim: 1. A compound of the formula wherein R signifies hydrogen,lower alkyl, lower alkanoyl, lower alkylsulfonyl, C to C cycloalkyl or Cto C cycloalkyl-lower alkyl; R signifies hydrogen, lower alkyl, C to Ccycloalkyl or C to C cycloalkyl-lower alkyl; R signifies fluorine,chlorine or lower alkoxy; X signifies an oxygen atom or a sulfur atom.

1. A COMPOUND OF THE FORMULA